Methods and compositions relating to adenosine receptors
Inventors
Sato, Aaron • Liu, Qiang • Axelrod, Fumiko • WANG, Linya
Assignees
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Publication Number
US-12202905-B2
Publication Date
2025-01-21
Expiration Date
Abstract
Provided herein are methods and compositions relating to adenosine A2A receptor libraries having nucleic acids encoding for a scaffold comprising an adenosine A2A binding domain. adenosine A2A receptor libraries described herein encode for immunoglobulins such as antibodies.
Core Innovation
The invention relates to an antibody or antibody fragment that binds to an adenosine 2A receptor, where the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL). The VH includes CDRH1 comprising the amino acid sequence of SEQ ID NO: 56, CDRH2 comprising the amino acid sequence of SEQ ID NO: 145, and CDRH3 comprising the amino acid sequence of SEQ ID NO: 234, and the VL includes CDRL1 comprising the amino acid sequence of SEQ ID NO: 323, CDRL2 comprising the amino acid sequence of SEQ ID NO: 412, and CDRL3 comprising the amino acid sequence of SEQ ID NO: 501.
The content further relates to adenosine 2A receptor-binding antibodies and antibody fragments with defined CDR sequences, binding potency, antagonistic cAMP activity, and cross-reactivity profiles for A2A versus hA2b/A3/hA2a. It also describes functional activity in primary T-cell activation, including EC50 in a primary T-cell activation assay.
The content additionally describes in vivo efficacy in colon carcinoma models, including tumor regression and immune cell infiltration and tumor-associated macrophage changes, including changes involving M1 tumor-associated macrophages and tumor-infiltrating lymphocytes such as CD8+ T cells. It also describes reformatting into IgG1/IgG4, including improved T-cell activation for IgG4.
Claims Coverage
The consolidated independent claim coverage centers on one adenosine 2A receptor-binding antibody or antibody fragment defined by six specifically identified CDR sequences, with dependent refinements described for quantitative binding and functional thresholds and additional sequence identity constraints.
Adenosine 2A receptor-binding antibody or fragment defined by VH and VL CDR sequences
An antibody or antibody fragment that binds to adenosine 2A receptor, wherein the heavy chain comprises a heavy chain variable region (VH) and the light chain comprises a light chain variable region (VL), with VH CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of SEQ ID NO: 56, 145, and 234, respectively, and VL CDRL1, CDRL2, and CDRL3 comprising the amino acid sequences of SEQ ID NO: 323, 412, and 501, respectively.
T cell activation potency threshold
An antibody or antibody fragment wherein the antibody has an IC50 of less than about 7.5 nM in a T cell activation assay.
Adenosine 2A receptor affinity threshold
An antibody or antibody fragment that binds to the adenosine 2A receptor with a dissociation constant (K_D) of less than about 25 nM.
Additional VH/VL identity constraints
An antibody or antibody fragment where the VH comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 590 and the VL comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 679.
Antibody format coverage for binding constructs
A method using an antibody selected from monoclonal, bi-specific, multispecific, grafted, humanized, synthetic, chimeric, single-chain Fvs (scFv), Fab, F(ab')2, Fv, diabody, disulfide-linked Fvs (sdFv), intrabody, or an antigen-binding fragment thereof.
Encoded nucleic acid
A nucleic acid encoding the antibody or antibody fragment described in claim 1.
Coverage centers on adenosine 2A receptor-binding antibodies defined by specific CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences, with refinements adding quantitative binding and functional thresholds, additional VH/VL sequence identity constraints, selectable antibody formats, and nucleic acids encoding the binding constructs.
Stated Advantages
Provides antibodies or antibody fragments that bind to the adenosine 2A receptor with defined VH and VL CDR sequences.
Provides quantitative binding or functional thresholds in specified assay contexts.
Documented Applications
Functional evaluation in cell assays, including cAMP assays.
Functional evaluation in T-cell activation assay contexts.
In vivo efficacy in colon carcinoma models, including tumor regression and immune cell infiltration and tumor-associated macrophage changes.
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